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Structure of HIV-1 reverse transcriptase cleaving RNA in an RNA/DNA hybrid.

ABSTRACT: HIV-1 reverse transcriptase (RT) contains both DNA polymerase and RNase H activities to convert the viral genomic RNA to dsDNA in infected host cells. Here we report the 2.65-Å resolution structure of HIV-1 RT engaging in cleaving RNA in an RNA/DNA hybrid. A preferred substrate sequence is absolutely required to enable the RNA/DNA hybrid to adopt the distorted conformation needed to interact properly with the RNase H active site in RT. Substituting two nucleotides 4 bp upstream from the cleavage site results in scissile-phosphate displacement by 4 Å. We also have determined the structure of HIV-1 RT complexed with an RNase H-resistant polypurine tract sequence, which adopts a rigid structure and is accommodated outside of the nuclease active site. Based on this newly gained structural information and a virtual drug screen, we have identified an inhibitor specific for the viral RNase H but not for its cellular homologs.

SUBMITTER: Tian L

PROVIDER: S-EPMC5777007 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Structure of HIV-1 reverse transcriptase cleaving RNA in an RNA/DNA hybrid.

Tian Lan L Kim Min-Sung MS Li Hongzhi H Wang Jimin J Yang Wei W

Proceedings of the National Academy of Sciences of the United States of America 20180102 3

HIV-1 reverse transcriptase (RT) contains both DNA polymerase and RNase H activities to convert the viral genomic RNA to dsDNA in infected host cells. Here we report the 2.65-Å resolution structure of HIV-1 RT engaging in cleaving RNA in an RNA/DNA hybrid. A preferred substrate sequence is absolutely required to enable the RNA/DNA hybrid to adopt the distorted conformation needed to interact properly with the RNase H active site in RT. Substituting two nucleotides 4 bp upstream from the cleavage ...[more]

PMID: 29295939

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